ISG15 deficiency and increased viral resistance in humans but not mice

Scott D. Speer, Zhi Li, Sofija Buta, Béatrice Payelle-Brogard, Li Qian, Frederic Vigant, Erminia Rubino, Thomas J. Gardner, Tim Wedeking, Mark Hermann, James Duehr, Ozden Sanal, Ilhan Tezcan, Nahal Mansouri, Payam Tabarsi, Davood Mansouri, Véronique Francois-Newton, Coralie F. Daussy, Marisela R. Rodriguez, Deborah J. Lenschow & 7 others Alexander Freiberg, Domenico Tortorella, Jacob Piehler, Benhur Lee, Adolfo García-Sastre, Sandra Pellegrini, Dusan Bogunovic

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

ISG15 is an interferon (IFN)-α/β-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-I 3-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/β signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.

Original languageEnglish (US)
Article number11496
JournalNature Communications
Volume7
DOIs
StatePublished - May 19 2016
Externally publishedYes

Fingerprint

immunity
interferon
Antiviral Agents
mice
Immunity
Interferons
Ubiquitins
proteins
Level control
fibroblasts
viruses
Fibroblasts
Viruses
Down-Regulation
magnetic permeability
requirements
Molecules
molecules
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Speer, S. D., Li, Z., Buta, S., Payelle-Brogard, B., Qian, L., Vigant, F., ... Bogunovic, D. (2016). ISG15 deficiency and increased viral resistance in humans but not mice. Nature Communications, 7, [11496]. https://doi.org/10.1038/ncomms11496

ISG15 deficiency and increased viral resistance in humans but not mice. / Speer, Scott D.; Li, Zhi; Buta, Sofija; Payelle-Brogard, Béatrice; Qian, Li; Vigant, Frederic; Rubino, Erminia; Gardner, Thomas J.; Wedeking, Tim; Hermann, Mark; Duehr, James; Sanal, Ozden; Tezcan, Ilhan; Mansouri, Nahal; Tabarsi, Payam; Mansouri, Davood; Francois-Newton, Véronique; Daussy, Coralie F.; Rodriguez, Marisela R.; Lenschow, Deborah J.; Freiberg, Alexander; Tortorella, Domenico; Piehler, Jacob; Lee, Benhur; García-Sastre, Adolfo; Pellegrini, Sandra; Bogunovic, Dusan.

In: Nature Communications, Vol. 7, 11496, 19.05.2016.

Research output: Contribution to journalArticle

Speer, SD, Li, Z, Buta, S, Payelle-Brogard, B, Qian, L, Vigant, F, Rubino, E, Gardner, TJ, Wedeking, T, Hermann, M, Duehr, J, Sanal, O, Tezcan, I, Mansouri, N, Tabarsi, P, Mansouri, D, Francois-Newton, V, Daussy, CF, Rodriguez, MR, Lenschow, DJ, Freiberg, A, Tortorella, D, Piehler, J, Lee, B, García-Sastre, A, Pellegrini, S & Bogunovic, D 2016, 'ISG15 deficiency and increased viral resistance in humans but not mice', Nature Communications, vol. 7, 11496. https://doi.org/10.1038/ncomms11496
Speer SD, Li Z, Buta S, Payelle-Brogard B, Qian L, Vigant F et al. ISG15 deficiency and increased viral resistance in humans but not mice. Nature Communications. 2016 May 19;7. 11496. https://doi.org/10.1038/ncomms11496
Speer, Scott D. ; Li, Zhi ; Buta, Sofija ; Payelle-Brogard, Béatrice ; Qian, Li ; Vigant, Frederic ; Rubino, Erminia ; Gardner, Thomas J. ; Wedeking, Tim ; Hermann, Mark ; Duehr, James ; Sanal, Ozden ; Tezcan, Ilhan ; Mansouri, Nahal ; Tabarsi, Payam ; Mansouri, Davood ; Francois-Newton, Véronique ; Daussy, Coralie F. ; Rodriguez, Marisela R. ; Lenschow, Deborah J. ; Freiberg, Alexander ; Tortorella, Domenico ; Piehler, Jacob ; Lee, Benhur ; García-Sastre, Adolfo ; Pellegrini, Sandra ; Bogunovic, Dusan. / ISG15 deficiency and increased viral resistance in humans but not mice. In: Nature Communications. 2016 ; Vol. 7.
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